The overall objective of the research proposed in this grant application is to examine the role of helix-loop-helix proteins in B-lineage development. The E2A proteins are helix-loop-helix proteins, which in B lymphocytes bind as homodimers. We have recently shown that the E2A proteins play essential roles throughout B cell development. Both E12 and E47 are required during the early stages prior to the onset of immunoglobulin (Ig) rearrangement. They have the ability to promote IgH and Ig kappa rearrangement. Finally, they are required to induce class switch recombination in activated B lineage cells. We propose to continue these studies. In particular we would investigate the relationship of E2A, EBF and Pax-5. We would examine how E2A proteins regulate Ig V(D)J recombination. We would assess the role of Id2 and Id3 in early B lineage development and examine how E2A and Id proteins are regulated during the pro-B to pre-B cell transition. We would clarify whether E12 or E47 or both are required for Ig isotype switching. Finally, we would examine how E2A protein levels are regulated in activated mature B lineage cells. Overall the dissection of the roles of E2A and Id in B cell development should help to clarify the mechanism of how HLH proteins regulate B lineage development.